Estriol (E3), sold under the brand name Ovestin among others, is an estrogen medication and naturally occurring steroid hormone which is used in menopausal hormone therapy. It is also used in veterinary medicine as Incurin to treat urinary incontinence due to estrogen deficiency in dogs. The medication is taken by mouth in the form of tablets, as a cream that is applied to the skin, as a cream or pessary that is applied in the vagina, and by injection into muscle.
Estriol is well-tolerated and produces relatively few adverse effects. Side effects may include breast tenderness, vaginal discomfort and discharge, and endometrial hyperplasia. Estriol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. It is an atypical and relatively weak estrogen, with much lower potency than estradiol. When present continuously at adequate concentrations however, estriol produces full estrogenic effects similarly to estradiol.
Estriol was first discovered in 1930, and was introduced for medical use shortly thereafter. Estriol esters such as estriol succinate are also used. Although it is less commonly employed than other estrogens like estradiol and conjugated estrogens, estriol is widely available for medical use in Europe and elsewhere throughout the world.
Medical uses Estriol is used in menopausal hormone therapy to treat menopausal symptoms, such as hot flashes, vulvovaginal atrophy, and dyspareunia (difficult or painful sexual intercourse). The benefits of estriol on bone mineral density and osteoporosis prevention have been inconsistent and are less clear. Estriol has been found to reduce the risk of urinary tract infections and other urogenital symptoms. A combination of estriol and lactobacilli as a dual estrogen and probiotic has been marketed for the treatment of vaginal atrophy and urinary tract infections.
Available forms (except USA) Estriol is available in oral tablet, vaginal cream, and vaginal suppository forms. It is also available over-the-counter or from compounding pharmacies in the form of topical creams. The medication is available both as estriol and in the form of estriol ester prodrugs such as estriol succinate, estriol acetate benzoate, and estriol tripropionate, as well as the polymeric ester prodrug polyestriol phosphate.
Estriol was originally marketed in the 1930s in the form of oral capsules containing 0.06, 0.12, or 0.24 mg estriol under the brand names Theelol (Parke-Davis) and Estriol (Lilly, Abbott). Subsequently, many decades later, oral tablets containing 0.35, 1, or 2 mg estriol were introduced under brand names such as Gynäsan, Hormomed, Ovestin, and Ovo-Vinces.
Contraindications
General contraindications of estrogens include breast cancer, endometrial cancer, and others. In animals, estriol is contraindicated during pregnancy and in ferrets.
Side effects Estriol is well-tolerated and produces relatively few adverse effects. Breast tenderness may sometimes occur as a side effect of estriol. Local reactions with vaginal estriol such as discomfort (irritation, burning, itching) and discharge may occur. Estriol may produce endometrial hyperplasia similarly to estradiol and other estrogens, and hence should be combined with a progestogen in women with intact uteruses to prevent this risk. However, it appears that typical clinical dosages of vaginal estriol are not associated with an important risk of endometrial proliferation or hyperplasia. As such, combination with a progestogen may not be needed in the case of vaginal estriol. Some studies suggest that this may also be true for oral estriol. However, dosage and frequency of administration, as well as meal consumption, may be determining factors as to whether or not estriol produces endometrial proliferation.
Overdose
Estrogens and other steroids are relatively safe in acute overdose. Estriol has been assessed in single oral doses of up to 75 mg. General symptoms of estrogen overdose in humans may include nausea, vomiting, vaginal bleeding, and reversible feminization. While there are no known studies describing the acute toxicity of estrogen overdose in dogs, this species is known to be more sensitive to the toxic effects of estrogens than humans and other animals. The most serious short-term adverse effect of estrogens in dogs is bone marrow suppression and consequent pancytopenia, which can be life-threatening.
Interactions
Interactions with estriol might be expected to be similar to those of estradiol. No interactions with estriol have been reported in animals. However, it should not be used in combination with other drugs that suppress bone marrow production in dogs.
Pharmacology
Pharmacodynamics Estriol is an estrogen, or an agonist of the estrogen receptors (ERs), ERα and ERβ. In terms of relative binding affinities (RBA) for the ERs compared to estradiol, it was found in one study to possess 11 to 14% of the RBA for the human ERα and 18 to 21% of the RBA for the human ERβ. Its relative transactivational capacities at the ERs compared to estradiol were 11% at ERα and 17% at ERβ. In addition to being a ligand of the classical nuclear ERs, estriol is an antagonist of the G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor (mER), at high concentrations (~1,000–10,000 μM). This is in contrast to estradiol, which is an agonist of this receptor. Like other estrogens, estriol does not importantly interact with other steroid hormone receptors.
Estriol is a much less potent estrogen than is estradiol, and is somewhat weak and atypical in its properties. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol. With clinical use, estriol is said to be weakly estrogenic in certain tissues, such as the liver and endometrium, but produces pronounced and full estrogenic responses in the vaginal epithelium. The medication has been found to reduce hot flashes, improve vaginal atrophy, reverse the postmenopausal decline in skin thickness and collagen content, suppress gonadotropin secretion, and produce proliferation of breast epithelium. Conversely, estriol does not consistently affect bone resorption or fracture risk, does not seem to increase breast density, and, at oral doses of 2 to 4 mg/day, does not affect liver proteins, lipid metabolism, or hemostatic parameters. Additionally, vaginal estriol does not appear to produce endometrial proliferation or increase the risk of endometrial hyperplasia, and some studies have found this to be the case for oral estriol as well. On the other hand, it appears that estriol may be able to stimulate the growth of active breast cancer. In rodents, estriol induces mammary gland development similar to that with estrone. By the oral route in women, estriol has approximately 30% of the potency of estradiol in terms of hot flashes relief and suppression of follicle-stimulating hormone secretion, and about 20% of the potency of estradiol on stimulation of liver production of high-density lipoprotein (HDL) cholesterol. A study of ovulation inhibition by estrogens in women found that prevention of ovulation occurred with 5 mg/day oral estriol in only 1 of 7 cycles. Due to its differing effects from those of estradiol, estriol may be considered a safer estrogen in certain regards.
The weak and atypical estrogenicity of estriol is thought to be related to its short duration in the body and hence the fact that it stays bound to the ER for a relatively short amount of time. Whereas estradiol remains bound to the ER for 6 to 24 hours with a single short-acting injection, estriol dissociates from the receptor much more rapidly and stays bound for only 1 to 6 hours. As a result, estriol can only induce estrogenic effects which require short-term interaction with the ERs. Induction of endometrial mitoses requires the ligand to remain bound for at least 9 to 12 hours, and this is thought to be responsible for the lack of endometrial proliferation with estriol in many studies. If estriol is delivered more continuously than a single administration per day however, for instance if it is given as a subcutaneous pellet, as a depot injection, or in multiple doses two or three times per day, this results in more sustained exposure to estriol and full estrogenic responses equivalent to those of estradiol occur. For these reasons, estriol has been described as a "short-acting" estrogen and it has been said that descriptors like "weak" and "impeded" are inaccurate. Consumption of food after oral administration of estriol also results in more prolonged exposure to estriol, due to enterohepatic recycling and resurgences in estriol levels. As such, if avoidance of endometrial hyperplasia or other full estrogenic effects is intended, it may be preferable to take estriol in a single dose, as low as possible, once per day at night before bedtime.
Although estriol is an estrogen, it has also been reported to have mixed agonist–antagonist or partial agonist activity at the ERs. On its own, it is said to be weakly estrogenic, but in the presence of estradiol, it has been found to be antiestrogenic. However, this is again due to the fact that estriol is a "short-acting" estrogen. If estriol is present continuously with estradiol, it shows no antagonism of estradiol. The co-administration of estriol with estradiol has been found not to influence the effects of the latter in women, including neither enhancing nor antagonizing the effects of estradiol.
Pharmacokinetics
Absorption Estriol has significant bioavailability, but its potency is limited by rapid metabolism and excretion and its relatively weak estrogenic activity. With oral administration, during first-pass metabolism, a considerable portion of estriol is conjugated via sulfation into estriol sulfate and rapidly excreted. Only about 10 to 20% of a dose of estriol remains in the circulation, and of this, only about 1 to 2% is present in its active, unconjugated form. Peak levels of estriol occur about 1 to 3 hours after an oral dose. Similarly to the case of progesterone, taking oral estriol with food greatly enhances its absorption. In addition, due to enterohepatic recycling, consuming a meal 4 hours after taking oral estriol can produce a second peak in estriol levels. Dosages of oral estriol of 4 to 10 mg have been found to result in a fairly large range of maximal estriol levels of 80 to 340 pg/mL. After a single oral dose of 8 mg estriol in postmenopausal women, maximal levels of 65 pg/mL estriol and 60 ng/mL estriol conjugates were produced within an hour. With continued daily administration, this increased to peak levels of 130 pg/mL estriol, whereas maximal levels of estriol conjugates remained at 60 ng/mL. Levels of estriol rapidly decreased to low levels following occurrence of peak levels. Consumption of a meal 4 hours after taking an oral dose of 8 mg estriol during continuous daily administration resulted in a second estriol peak 2 hours later of 120 pg/mL, with estriol levels declining slowly thereafter to about 25 pg/mL after 24 hours.